2-Amino-6-chloropurine is an essential intermediate in the preparation of nucleoside-analogue pharmaceutical compositions which are effective antiviral agents, such as Pencyclovir and Famicyclovir.
Numerous methods of preparing such 2-amino-6-halopurines are already known from the prior art. Thus, British Patent 767216 describes a process in which guanine is first reacted with phosphorus pentasulphide, thereby introducing a mercapto group into the 6-position of the purine system. Subsequent treatment with chlorine leads to the corresponding 6-chloro derivative in the second step of the reaction.
However, this method of synthesis has the disadvantage, among others, that the decomposition products of phosphorus pentasulphide have an unpleasant odour, which necessarily involves the risk of undesirable environmental effects. Other disadvantages of this process arise from the low yield and from the fact that the thioguanine which is obtained in the first reaction step has been shown to have mutagenic properties. In another process, 2-amino-6-mercaptopurine is converted into the corresponding 6-thiomethyl derivative using methyl iodide; subsequent treatment with chlorine leads to the desired 6-chloro derivative, as in the process described above (J. Am. Chem. Soc. 79 (1957) 2185; J. Am. Chem. Soc. 82(1960) 2633), but this method of synthesis does not get around the disadvantages of the process described above.
In a fundamentally different method of production, guanine is reacted with phosphorus oxychloride in the presence of a quaternary ammonium salt, which is a direct method of producing the 2-amino-6-chloropurine (published Japanese Application No. 227583/1986). However, this procedure has the disadvantage that the yield is only in the range from 30 to 42%, owing to the dissolving characteristics of the guanine.
A more recent process (EP 0 543 095) describes a reaction route via a different type of intermediate product. Here, guanine is reacted in the presence of a halogenating agent with N,N-dialkylformyl compounds such as N,N-dimethylformamide, N,N-diethylformamide, N-methylformanilide, N,N-dimethylacetamide, N-formylpiperazine and N-formylmorpholine.
The subsequent hydrolysis makes it possible, by this method, to obtain 2-amino-6-chloropurine, inter alia, which should thus be accessible in a maximum yield of up to 70% on the basis of laboratory-scale experiments.
Another recently disclosed method of production starts from 2,9-diacetylguanine (WO 93/15075). Here, 2,9-diacetylguanine is reacted, inter alia, in the presence of a phase transfer catalyst, e.g. triethylmethylammonium chloride, with a chlorinating agent such as 2 to 4 equivalents of phosphorus oxychloride. Then, in the second reaction step, both acyl groups are hydrolytically cleaved using aqueous sodium hydroxide solution. Using this method, 2-amino-6-chloropurine can be obtained in a yield of about 75%.
Also recently disclosed was a process which starts from the guanine precursor 2,4-diamino-6-hydroxypyrimidine and proceeds, in a manner known per se, via the intermediate stages of 2,4-diamino-6-chloropyrimidine and 2,4-diamino-5-nitro-6-chloropyrimidine. The latter has to be catalytically hydrogenated and cyclised with a reactive formic acid derivative, such as an orthoester. This process has the particular disadvantage, compared with conventional guanine synthesis, that nitrogenation has to be carried out instead of nitrosation (DE OS 41 42 568).
In addition to the disadvantages mentioned above, the processes known from the prior art have another disadvantage, particularly affecting those processes which start with guanine, in that the unreacted guanine can only be removed at considerable expense.